ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.2920C>T (p.Arg974Cys) (rs397514558)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000548224 SCV000627874 pathogenic Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection 2017-02-17 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 974 of the FBN1 protein (p.Arg974Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the literature co-segregating with disease in a family affected with isolated ectopia lentis (PMID: 22539873). It has also been reported in unrelated individuals affected with Marfan syndrome (PMID: 17657824, 17627385). ClinVar contains an entry for this variant (Variation ID: 39667). This variant generates a cysteine residue in an epidermal-growth-factor (EGF)–like domain of the FBN1 protein. Cysteine residues in these domains have been shown to be involved in the formation of disulfide bridges, which are critical for FBN1 protein structure and stability (PMID: 4750422, 16677079). Cysteine creating variants in these domains have been shown to affect protein stability and are overrepresented among individuals with Marfan syndrome (PMID: 15161917, 16571647, 17701892). For these reasons, this variant has been classified as Pathogenic.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000726909 SCV000704117 pathogenic not provided 2016-12-28 criteria provided, single submitter clinical testing
Ambry Genetics RCV000621942 SCV000738929 pathogenic Cardiovascular phenotype 2017-10-26 criteria provided, single submitter clinical testing The p.R974C pathogenic mutation (also known as c.2920C>T), located in coding exon 24 of the FBN1 gene, results from a C to T substitution at nucleotide position 2920. The arginine at codon 974 is replaced by cysteine, an amino acid with highly dissimilar properties, and is located in the TGFBP#03 domain. The majority of FBN1 mutations identified to date have involved the substitution or generation of cysteine residues (Collod-Béroud G et al. Hum. Mut. 2003:22(3):199-208). This particular mutation has been reported in a number of Marfan syndrome (MFS) and ectopia lentis (EL) cohorts (Comeglio P et al. Hum. Mutat. 2007;28:928; Howarth R et al. Genet. Test. 2007;11:146-52; Stheneur C et al. Eur. J. Hum. Genet. 2009;17:1121-8; Li J et al. Mol. Vis. 2014;20:1017-24; Vatti L et al. Am. J. Med. Genet. A. 2017;173:2995-3002). This variant also segregated with disease in one large Chinese family (Yang G et al. Mol. Vis. 2012;18:945-50). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Center for Human Genetics, Inc,Center for Human Genetics, Inc RCV000032871 SCV000781346 pathogenic Marfan syndrome 2016-11-01 criteria provided, single submitter clinical testing
RBHT Clinical Genetics and Genomics Laboratory,Royal Brompton and Harefield NHS Foundation Trust RCV000032871 SCV000845663 likely pathogenic Marfan syndrome 2017-07-27 criteria provided, single submitter clinical testing The FBN1 c.2920C>T variant has previously been reported in 9 affected members of a 5 generation family with isolated ectopia lentis (Yang et al. Mol Vis. 2012;18:945-50) and a single patient with Marfan syndrome with major skeletal, ocular and cardiovascular manifestations (Comeglio et al. Hum Mutat. 2007 ;28(9):928). It has not been detected in approximately 120,000 individuals in control populations (gnomAD database). In silico tools predict the variant will adversely affect protein structure and function and it affects a highly conserved TGFB binding domain. This variant is therefore likely to be pathogenic, but may be associated with a variable phenotype. - Other Disease Reports - This variant has been linked to other diseases: Ectopia lentis (pubmed: 22539873) - Missense Effect Predictions - 87.5% (7/8) of algorithms have predicted that this variant will adversely affect protein function
Color Health, Inc RCV001186221 SCV001352587 likely pathogenic Familial thoracic aortic aneurysm and aortic dissection 2020-02-25 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001192805 SCV001361165 pathogenic Marfan Syndrome/Loeys-Dietz Syndrome/Familial Thoracic Aortic Aneurysms and Dissections 2019-09-16 criteria provided, single submitter clinical testing Variant summary: FBN1 c.2920C>T (p.Arg974Cys) results in a non-conservative amino acid change located in the TB domain (IPR017878) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251458 control chromosomes (gnomAD). c.2920C>T has been reported in the literature in multiple individuals affected with Marfan Syndrome (eg- Comeglio_2007, Howarth_2007, Li_2014, Vatti_2017). The variant has also been reported to segregate with disease in a family with Ectopia Lentis phenotype without other symptoms of Marfan Syndrome (Yang_2012). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar (evaluation after 2014) and cited the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001287328 SCV001474003 pathogenic none provided 2020-02-25 criteria provided, single submitter clinical testing The FBN1 c.2920C>T; p.Arg974Cys variant (rs397514558) is reported in the literature in several individuals affected with Marfan syndrome (Comeglio 2007, Stheneur 2009). This variant is also reported to segregate in all affected members of a large, multigenerational kindred affected with ectopia lentis (Yang 2012). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The arginine at codon 974 is moderately conserved, it occurs in one of the TGF-beta binding (TB) domains (Yuan 1997), and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. TB domains contain eight conserved cysteine residues and the disulfide bridges formed between these residues are essential for protein folding; loss of one of these cysteines or creation of a new cysteine in this domain may interfere with proper disulfide bridge formation, disrupting protein structure (Yuan 1997). Accordingly, the revised Ghent nosology for Marfan syndrome lists missense variants creating or affecting cysteine residues as one of the criteria for classification of a variant as pathogenic (Loeys 2010). Based on available information, this variant is considered to be pathogenic. References: Comeglio P et al. The importance of mutation detection in Marfan syndrome and Marfan-related disorders: report of 193 FBN1 mutations. Hum Mutat. 2007 Sep;28(9):928. Loeys BL et al. The revised Ghent nosology for the Marfan syndrome. J Med Genet. 2010 47(7): 476-85. Stheneur C et al. Identification of the minimal combination of clinical features in probands for efficient mutation detection in the FBN1 gene. Eur J Hum Genet. 2009 Sep;17(9):1121-8. Yang G et al. A novel FBN1 mutation in a Chinese family with isolated ectopia lentis. Mol Vis. 2012;18:945-50. Yuan X et al. Solution structure of the transforming growth factor beta-binding protein-like module, a domain associated with matrix fibrils. EMBO J. 1997 Nov 17;16(22):6659-66.
OMIM RCV000032871 SCV000056641 pathogenic Marfan syndrome 2012-01-01 no assertion criteria provided literature only
OMIM RCV000172857 SCV000223833 pathogenic Ectopia lentis, isolated, autosomal dominant 2012-01-01 no assertion criteria provided literature only
Center for Medical Genetics Ghent,University of Ghent RCV000032871 SCV000786902 likely pathogenic Marfan syndrome 2017-11-07 no assertion criteria provided clinical testing

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